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Am J Physiol Cell Physiol 281: C1096-C1105, 2001;
0363-6143/01 $5.00
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Vol. 281, Issue 4, C1096-C1105, October 2001

Regulation and distribution of MAdCAM-1 in endothelial cells in vitro

Tadayuki Oshima1, Kevin P. Pavlick1, F. Stephen Laroux1, S. Kris Verma2, Paul Jordan2, Matthew B. Grisham1, Larry Williams3, and J. Steven Alexander1

Departments of 1 Molecular and Cellular Physiology and 2 Gastroenterology, Louisianna State University Health Sciences Center, Shreveport, Louisiana, 71130-3932; and 3 Guilford Pharmaceuticals, Baltimore, Maryland 21224

Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is a 60-kDa endothelial cell adhesion glycoprotein that regulates lymphocyte trafficking to Peyer's patches and lymph nodes. Although it is widely agreed that MAdCAM-1 induction is involved in chronic gut inflammation, few studies have investigated regulation of MAdCAM-1 expression. We used two endothelial lines [bEND.3 (brain) and SVEC (high endothelium)] to study the signal paths that regulate MAdCAM-1 expression in response to tumor necrosis factor (TNF)-alpha using RT-PCR, blotting, adhesion, and immunofluorescence. TNF-alpha induced both MAdCAM-1 mRNA and protein in a dose- and time-dependent manner. This induction was tyrosine kinase (TK), p42/44, p38 mitogen-activated protein kinase (MAPK), and nuclear factor (NF)-kappa B/poly-ADP ribose polymerase (PARP) dependent. Because MAdCAM-1 is regulated via MAPKs, we examined mitogen/extracellular signal-regulated kinase (MEK)-1/2 activation in SVEC. We found that MEK-1/2 is activated by TNF-alpha within minutes and is dependent on TK and p42/44 MAPKs. Similarly, TNF-alpha activated NF-kappa B through TK, p42/44, p38 MAPKs, and PARP pathways in SVEC cells. MAdCAM-1 was also shown to be frequently distributed to endothelial junctions both in vitro and in vivo. Cytokines like TNF-alpha stimulate MAdCAM-1 in high endothelium via TK, p38, p42/22 MAPKs, and NF-kappa B/PARP. MAdCAM-1 expression requires NF-kappa B translocation through both direct p42/44 and indirect p38 MAPK pathways in high endothelial cells.

mucosal addressin cell adhesion molecule-1


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